Hypothalamic Somatostatin and Growth Hormone-Releasing Hormone mRNA Expression Depend upon GABAA Receptor Expression in the Developing Mouse

Gonadal steroids exert an important regulatory influence upon the biosynthetic and secretory activity of the somatostatin and growth hormone-releasing hormone (GHRH) neurons controlling the release of growth hormone. It is hypothesized that some of these effects occur in an indirect transsynaptic manner through the steroid regulation of GAGAergic inputs to these cells. Using GABA<sub>A</sub> receptor γ<sub>2</sub> subunit knockout mice (γ<sub>2</sub><sup>–/–</sup>), which exhibit marked deficiencies in GABA<sub>A</sub> receptor functioning, we have examined here whether signaling through the GABA<sub>A</sub> receptor has any role in maintaining normal levels of somatostatin and GHRH mRNA expression in vivo. In situ hybridization experiments using <sup>35</sup>S-labeled oligonucleotide probes revealed that cellular levels of somatostatin mRNA in the periventricular nucleus were significantly (p < 0.01) reduced by 16% in newborn γ<sub>2</sub><sup>–/–</sup> mice compared with wild-type litter mates (γ<sub>2</sub><sup>+/+</sup>). Somatostatin mRNA expression in the striatum was not changed. Cellular levels of GHRH mRNA expression in the arcuate nucleus were significantly (p < 0.05) reduced by 30% in γ<sub>2</sub><sup>–/–</sup> compared with γ<sub>2</sub><sup>+/+</sup> mice. These results demonstrate that deletion of the γ<sub>2</sub> subunit of the GABA<sub>A</sub> receptor reduces somatostatin and GHRH mRNA expression within the hypothalamopituitary axis and indicate that GABA exerts a tonic stimulatory influence upon both somatostatin and GHRH biosynthesis in vivo in the neonatal mouse.

[1]  H. Delemarre-van de Waal,et al.  Absence of Androgen Receptor in the Growth Hormone Releasing Hormone‐Containing Neurones in the Rat Mediobasal Hypothalamus , 2001, Journal of neuroendocrinology.

[2]  M. J. Sickel.  Excitatory GABA as a Mediator of Steroid-Induced Brain Sexual Differentiation , 2001 .

[3]  J. Kamegai,et al.  Estrogen receptor (ER)alpha, but not ERbeta, gene is expressed in growth hormone-releasing hormone neurons of the male rat hypothalamus. , 2001, Endocrinology.

[4]  W. Sieghart,et al.  Role of the GABAA receptor γ2 subunit in the development of gonadotropin‐releasing hormone neurons in vivo , 2000, The European journal of neuroscience.

[5]  S. Peineau,et al.  Somatostatin modulation of excitatory synaptic transmission between periventricular and arcuate hypothalamic nuclei in vitro. , 2000, Journal of neurophysiology.

[6]  D. Hoyer,et al.  Involvement of the Sst 1 Somatostatin Receptor Subtype in the Intrahypothalamic Neuronal Network Regulating Growth Hormone Secretion : An in Vitro and in Vivo Antisense Study , 2000 .

[7]  L. Doncarlos,et al.  Sexually Dimorphic Ontogeny of GABAergic Influences on Periventricular Somatostatin Neurons , 1999, Neuroendocrinology.

[8]  Nurhidayat,et al.  Sex differentiation of growth hormone-releasing hormone and somatostatin neurons in the mouse hypothalamus: an immunohistochemical and morphological study , 1999, Brain Research.

[9]  Gillies,et al.  Ontogeny and Sexual Differentiation of Somatostatin Biosynthesis and Secretion in the Hypothalamic Periventricular‐Median Eminence Pathway , 1999, Journal of neuroendocrinology.

[10]  Gillies,et al.  Correlation of Hypothalamic Somatostatin mRNA Expression and Peptide Content with Secretion: Sexual Dimorphism and Differential Regulation by Gonadal Factors , 1999, Journal of neuroendocrinology.

[11]  Bernhard Lüscher,et al.  Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin , 1998, Nature Neuroscience.

[12]  B. E. Wee,et al.  Growth Hormone Releasing Hormone Expression During Postnatal Development in Growth Hormone-Deficient Ames Dwarf Mice:mRNA in situ Hybridization , 1998, Neuroendocrinology.

[13]  A. Herbison,et al.  Estrogen-dependent ontogeny of sex differences in somatostatin neurons of the hypothalamic periventricular nucleus. , 1998, Endocrinology.

[14]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[15]  A. Herbison.  Estrogen Regulation of GABA Transmission in Rat Preoptic Area , 1997, Brain Research Bulletin.

[16]  T. Wagner,et al.  A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  X. Leinekugel,et al.  GABAA, NMDA and AMPA receptors: a developmentally regulated `ménage à trois' , 1997, Trends in Neurosciences.

[18]  B. E. Wee,et al.  Hypophysiotropic somatostatin expression during postnatal development in growth hormone-deficient Ames dwarf mice: mRNA in situ hybridization. , 1997, Neuroendocrinology.

[19]  A. Aguzzi,et al.  Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  A. Herbison.  Sexually Dimorphic Expression of Androgen Receptor Immunoreactivity by Somatostatin Neurones in Rat Hypothalamic Periventricular Nucleus and Bed Nucleus of the Stria Terminalis , 1995, Journal of neuroendocrinology.

[21]  C. Rougeot,et al.  GABAA and NMDA receptor activation controls somatostatin messenger RNA expression in primary cultures of hypothalamic neurons. , 1994, Neuroendocrinology.

[22]  S. Augood,et al.  Expression of GABAA receptor α 2 sub-unit mRNA by periventricular somatostatin neurones in the rat hypothalamus , 1994, Neuroscience Letters.

[23]  J. Argente,et al.  Differential effects of the neonatal and adult sex steroid environments on the organization and activation of hypothalamic growth hormone-releasing hormone and somatostatin neurons. , 1993, Endocrinology.

[24]  C. Rougeot,et al.  GABA inhibition of somatostatin gene expression in cultured hypothalamic neurones. , 1993, Neuroreport.

[25]  L. Donahue,et al.  Growth hormone deficiency in 'little' mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4. , 1993, The Journal of endocrinology.

[26]  J. Bertherat,et al.  Regulation of somatostatin synthesis by GABAA receptor stimulation in mouse brain. , 1992, Brain research. Molecular brain research.

[27]  W Wisden,et al.  The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  R. Steiner,et al.  Sexual dimorphism of growth hormone-releasing hormone and somatostatin gene expression in the hypothalamus of the rat during development. , 1991, Endocrinology.

[29]  L. Kaplan,et al.  Sexually dimorphic expression of the growth hormone-releasing hormone gene is not mediated by circulating gonadal hormones in the adult rat. , 1991, Endocrinology.

[30]  P. Emson,et al.  Distribution of somatostatin mRNA in the rat nervous system as visualized by a novel non-radioactive in situ hybridization histochemistry procedure , 1990, Neuroscience.

[31]  J. Simard,et al.  Multihormonal control of pre-pro-somatostatin mRNA levels in the periventricular nucleus of the male and female rat hypothalamus. , 1990, Neuroendocrinology.

[32]  R. Steiner,et al.  Somatostatin messenger RNA in hypothalamic neurons is increased by testosterone through activation of androgen receptors and not by aromatization to estradiol. , 1990, Neuroendocrinology.

[33]  J. Coyle,et al.  Developmental expression of somatostatin in mouse brain. II. In situ hybridization. , 1990, Brain research. Developmental brain research.

[34]  D K Clifton,et al.  Sexual dimorphism and testosterone-dependent regulation of somatostatin gene expression in the periventricular nucleus of the rat brain. , 1989, Endocrinology.

[35]  J. Willoughby,et al.  Ultrastructural evidence for gamma aminobutyric acid-immunoreactive synapses on somatostatin-immunoreactive perikarya in the periventricular anterior hypothalamus. , 1987, Neuroendocrinology.

[36]  J. Jansson,et al.  Sexual dimorphism in the control of growth hormone secretion. , 1985, Endocrine reviews.